Heterocycles, their preparation and their use

ABSTRACT

The invention concerns heterocyclic compounds of the general formula (I) in which A, B, R, R 2 , R 3 , W, Y, Z 1 , Z 2  and r are as defined in the description, methods of preparing them and their use as inhibitors of thrombocyte aggregation, the metastization of carcinoma cells and the binding of osteoclasts on bone surfaces. ##STR1##

This is a national stage application of PCT/EP94/00481 filed Feb. 19,1994 and published as WO 94/21607.

The present invention relates to substituted hetero-cycles, theirpreparation and their use as medicines, in particular as inhibitors ofblood platelet aggregation.

EP-A 449 079 and EP-A 530 505 describe hydantoin derivatives which haveplatelet aggregation-inhibiting effects. EP-A 512 831 describescompounds which prevent fibrinogen binding to blood platelets and, as aresult, the aggregation of the platelets. Further investigations showedthat the compounds of the present invention are also potent inhibitorsof blood platelet aggregation.

The present invention relates to novel heterocycles of the generalformula I ##STR2## in which Z¹ denotes ##STR3## Z² denotes ##STR4## or--CH₂ --; Y denotes --(CH₂)_(m) CO--, where m stands for an integer from1 to 4, or denotes --CHR^(s) --CO-- or ##STR5## r denotes an integerfrom 0 to 3; A denotes --CHR¹ --, --NR¹ -- or X¹ --C₆ H₄ --CH═C<;

B denotes --CH₂ -- or --O--;

W denotes --COW¹, tetrazolyl, --SO₂ --OH or --SO₂ NHR⁹ ;

W¹ denotes hydroxyl, (C₁ -C₂₈)-alkoxy, (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkoxy,which can also be substituted in the aryl radical, optionallysubstituted (C₆ -C₁₄)-aryloxy, amino or mono- or di-((C₁-C₁₈)-alkyl)amino;

R denotes hydrogen or (C₁ -C₆)-alkyl;

R¹ denotes ##STR6## or --(CH₂)_(n) --NH--X or --(CH₂)_(p) --C₆ H₄--(CH₂)_(q) --NH--X or --(CH₂)_(p) --C(═NX)--NH₂ or --(CH₂)_(p) --C₆ H₄--(CH₂)_(q) --C(═NX)--NH₂, in which n stands for a number from 1 to 6, pand q independently of one another stand for a number from 0 to 3 and tstands for a number from 0 to 2, but where, if A denotes --CHR¹ -- or--NR¹, B and Z² denote --CH₂ --, Y denotes --(CH₂)_(m) CO--, in which mis an integer from 1 to 4, R denotes hydrogen and r is the number 1,then, not at the same time

R¹ can denote ##STR7## or --(CH₂)_(n') NH--X or --(CH₂)_(p')--C(═NX)--NH₂, in which n' stands for a number from 1 to 4, p' standsfor a number from 1 to 3 and t' stands for the numbers 1 or 2;

X denotes hydrogen, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkylcarbonyl, (C₁-C₆)-alkoxycarbonyl, (C₁ -C₁₈)-alkylcarbonyloxy-(C₁ -C₆)-alkoxycarbonyl,optionally substituted (C₆ -C₁₄)-arylcarbonyl, optionally substituted(C₆ -C₁₄)-aryloxycarbonyl, (C₆ -C₁₄)-aryl-(C₁ -C₆)-alkoxycarbonyl, whichcan also be substituted in the aryl radical, cyano, hydroxyl, (C₁-C₆)-alkoxy or amino or a radical of the formula II

    R'--NH--C(═N--R")--,                                   (II)

where R' and R" independently of one another stand for hydrogen, (C₁-C₆)-alkyl, trifluoro-(C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxycarbonyl, (C₁-C₆)-alkylcarbonyl, optionally substituted (C₆ -C₁₄)-arylcarbonyl, (C₁-C₁₈)-alkylcarbonyloxy-(C₁ -C₆)-alkoxycarbonyl, optionally substituted(C₆ -C₁₄)-aryloxycarbonyl, (C₆ -C₁₄)-aryl-(C₁ -C₆)-alkoxycarbonyl, whichcan also be substituted in the aryl radical, cyano, hydroxyl, (C₁-C₆)-alkoxy or amino;

X¹ denotes --(CH₂)_(q) --NH--X or --(CH₂)_(p) --C(═NX)--NH₂ in which pand q stand for a number from 0 TO 3;

R² denotes hydrogen, (C₁ -C₄)-alkyl or phenyl, where the (C₁ -C₄)-alkyland the phenyl can be unsubstituted or mono- or polysubstituted byidentical or different radicals from the series hydroxyl, amino, (C₁-C₄)-alkoxy, imidazolyl, indolyl, pyrrolidinyl, hydroxypyrrolidinyl,phenyl or halogen;

R³ denotes hydrogen, --COOR⁴, --CO--N(CH₃)R⁴ or --CO--NH--R⁴ ;

R⁴ denotes hydrogen or (C₁ -C₂₈)-alkyl, which can optionally be mono- orpolysubstituted by identical or different radicals from the serieshydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C₁-C₁₈)-alkyl)aminocarbonyl, amino-(C₂ -C₁₈)-alkylaminocarbonyl, amino-(C₁-C₃)-alkylphenyl-(C₁ -C₃)-alkylaminocarbonyl, (C₁-C₁₈)-alkylcarbonylamino-(C₁ -C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl, (C₁ -C₁₈)-alkylcarbonylamino-(C₂-C₁₈)-alkylaminocarbonyl, (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkoxycarbonyl, whichcan also be substituted in the aryl radical, amino, mercapto, (C₁-C₁₈)-alkoxy, (C₁ -C₁₈)-alkoxycarbonyl, optionally substituted (C₃-C₈)-cycloalkyl, halogen, nitro, trifluoromethyl or by the radical R⁵,where

R⁵ denotes optionally substituted (C₆ -C₁₄)-aryl, (C₆ -C₁₄)-aryl-(C₁-C₈)-alkyl, optionally substituted in the aryl radical, a mono- orbicyclic 5- to 12-membered heterocyclic ring, which can be aromatic,partially hydrogenated or completely hydrogenated and which can containone, two or three identical or different heteroatoms from the seriesnitrogen, oxygen and sulphur, a radical R⁶ or a radical R⁶ CO--, wherethe aryl and, independently thereof, the heterocyclic radical can bemono- or polysubstituted by identical or different radicals from theseries (C₁ -C₁₈)-alkyl, (C₁ -C₁₈)-alkoxy, halogen, nitro, amino ortrifluoromethyl;

R⁶ denotes --NR⁷ R⁸, --OR⁷, --SR⁷, --SO₂ --OH, --SO₂ --NHR⁹, tetrazolyl,an amino acid side chain, a natural or unnatural amino acid, imino acid,optionally N--(C₁ -C₈)-alkylated or N--((C₆ -C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acid radical or a dipeptide radical, which canalso be substituted in the aryl radical and/or in which the peptide bondcan be reduced to --NH--CH₂ --, and also their esters and amides, wherefree functional groups can optionally be replaced by hydrogen orhydroxymethyl or protected by protective groups customary in peptidechemistry;

R⁷ denotes hydrogen, (C₁ -C₁₈)-alkyl, (C₆ -C₁₄ -aryl-(C₁ -C₈)-alkyl, (C₁-C₁₈)-alkylcarbonyl, (C₁ -C₁₈)-alkoxycarbonyl, (C₆ -C₁₄)-arylcarbonyl,(C₆ -C₁₄)-aryl-(C₁ -C₈)-alkylcarbonyl or (C₆ -C₁₄)-aryl-(C₁-C₁₈)-alkoxycarbonyl, where the alkyl groups can optionally besubstituted by an amino group and/or where the aryl radicals can bemono- or polysubstituted, preferably mono- substituted, by identical ordifferent radicals from the series (C₁ -C₈)-alkyl, (C₁ -C₁₈)-alkoxy,halogen, nitro, amino and trifluoromethyl, a natural or unnatural aminoacid, imino acid, optionally N--(C₁ -C₈)-alkylated or N--((C₆-C₁₄)-aryl-(C₁ -C₈)-alkylated) azaamino acid radical or a dipeptideradical, which can also be substituted in the aryl radical and/or inwhich the peptide bond can be reduced to --NH--CH₂ --;

R⁸ denotes hydrogen, (C₁ -C₁₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl or (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkyl, which can also besubstituted in the aryl radical;

R⁹ denotes hydrogen, aminocarbonyl, (C₁ -C₁₈)-alkylaminocarbonyl, (C₃-C₈)-cycloalkylaminocarbonyl, (C₁ -C₁₈)-alkyl or (C₃ -C₈)-cycloalkyl;

R^(S) denotes an amino acid side chain; and their physiologicallytolerable salts.

Cycloalkyl radicals are in particular cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, which, however, canalso be substituted by, for example, (C₁ -C₄)-alkyl. Examples ofsubstituted cycloalkyl radicals are 4-methylcyclohexyl and2,3-dimethylcyclopentyl.

Alkyl radicals can be straight-chain or branched. This also applies ifthey carry substituents or occur as substituents of other radicals.Examples of suitable (C₁ -C₂₈)-alkyl radicals are: methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl,tridecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, eicosyl,docosyl, tricosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl,isopropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl,2,3,5-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferredalkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl.

(C₆ -C₁₄)-aryl groups are, for example, phenyl, naphthyl, biphenylyl orfluorenyl, phenyl and naphthyl being preferred. The same applies toradicals such as aralkyl or arylcarbonyl. Aralkyl radicals are inparticular benzyl and also 1- and 2-naphthylmethyl, which can also besubstituted. Substituted aralkyl radicals are, for example, halobenzylor (C₁ -C₄)-alkoxybenzyl.

If phenyl is disubstituted, the substituents can be in the 1,2-, 1,3- or1,4-position relative to one another. The 1,3- and the 1,4-positions arepreferred.

Mono- or bicyclic 5- to 12-membered heterocyclic rings are, for example,pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl,indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl or a benzo-fused or cyclopenta-,cyclohexa- or cyclohepta-fused derivative of these radicals.

These heterocycles can be substituted on one nitrogen atom by (C₁-C₇)-alkyl, e.g. methyl or ethyl, phenyl or phenyl-(C₁ -C₄)-alkyl, e.g.benzyl and/or on one or more carbon atoms by (C₁ -C₄)-alkyl, halogen,hydroxyl, (C₁ -C₄)-alkoxy, e.g. methoxy, phenyl-(C₁ -C₄)-alkoxy, e.g.benzyloxy, or oxo and can be aromatic or partially or completelysaturated. Nitrogen heterocycles can also be present as N-oxides.

Radicals of this type, are, for example, 2- or 3-pyrrolyl,phenylpyrrolyl, e.g. 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl,4-imidazolyl, methylimidazolyl, e.g. 1-methyl-2-, 4- or 5-imidazolyl,1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide,2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted2-indolyl, e.g. 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-,5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or 3-indolyl,4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl,2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl orbenzothiazolyl. Partially hydrogenated or completely hydrogenatedheterocyclic rings are, for example, dihydropyridinyl, pyrrolidinyl,e.g. 2-, 3- or 4-(N-methylpyrrolidinyl), piperazinyl, morpholinyl,thiomorpholinyl, tetrahydrothienyl or benzodioxolanyl.

Halogen stands for fluorine, chlorine, bromine or iodine, in particularfor fluorine or chlorine.

Natural and unnatural amino acids can be present, if chiral, in the D-or L-form. α-Amino acids are preferred. Examples which may be mentioned(cf. Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Volume XV/1 and 2, Stuttgart, 1974) are:

Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala,βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze,Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap, Dapm,Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln,hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr,Hyl, Hyp, 3Hyp,

Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys, ΔLys, Met, Mim, Min,nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, ΔPro, Pse,Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, βThi, Thr Thy, Tbx,Tia, Tle, Tly, Trp, Trta, Tyr, Val, Tbg, Npg, Chg, Cha, Thia,2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid,2-(p-chlorophenyl)aminoacetic acid.

Amino acid side chains are understood as meaning side chains of naturalor unnatural amino acids. Azaamino acids are natural or unnatural aminoacids in which the central component ##STR8## is replaced by ##STR9##

Suitable radicals of an imino acid are in particular radicals ofheterocycles from the following group: pyrrolidine-2-carboxylic acid;piperidine-2-carboxylic acid; tetrahydroisoquinoline-3-carboxylic acid;decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylicacid; decahydroquinoline-2-carboxylic acid;octahydrocyclopenta[b]pyrrole-2-carboxylic acid;2-azabicyclo[2.2.2]octane-3-carboxylic acid;2-azabicyclo[2.2.1]heptane-3-carboxylic acid;2-azabicyclo-[3.1.0]hexane-3-carboxylic acid;2-azospiro[4.4]nonane-3-carboxylic acid;2-azaspiro[4.5]decane-3-carboxylic acid;spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;2-azatricyclo[4.3.0.1.^(6'9) ]decane-3-carboxylic acid;decahydrocyclohepta[b]pyrrole-2-carboxylic acid;decahydrocycloocta[c]pyrrole-2-carboxylic acid;octahydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine- 3-carboxylic acid; hydroxypyrrolidine-2-carboxylic acid;which all can be optionally substituted (see following formulae):##STR10##

The heterocycles on which the abovementioned radicals are based aredisclosed, for example, in U.S. Pat. Nos. 4,344,949; 4,374,847;4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164;EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A111,873; EP-A 271,865 and EP-A 344,682.

Dipeptides can contain natural or unnatural amino acids, imino acids andalso azaamino acids as components. Furthermore, the natural or unnaturalamino acids, imino acids, azaamino acids and dipeptides can also bepresent as esters or amides, such as e.g. methyl ester, ethyl ester,isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester,ethylamide, semicarbazide or ω-amino-(C₄ -C₈)-alkylamide.

Functional groups of the amino acids, imino acids and dipeptides can bepresent in protected form. Suitable protective groups such as e.g.urethane protective groups, carboxyl protective groups and side chainprotective groups are described in Hubbuch, Kontakte (Merck) 1979, No.3, pages 14 to 23 and in Bullesbach, Kontakte (Merck) 1980, No. 1, pages23 to 35. The following may be mentioned in particular: Aloc, Pyoc,Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO₂), Z(Hal_(n)),Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob,Pic, Trt.

Physiologically tolerable salts of the compounds of the general formulaI are in particular pharmaceutically utilizable or non-toxic salts.

Such salts are formed, for example, from compounds of the generalformula I which contain acidic group, e.g. carboxyl, with alkali metalsor alkaline earth metals, such as e.g. Na, K, Mg and Ca, and also withphysiologically tolerable organic amines, such as e.g. triethylamine,ethanolamine or tris(2-hydroxyethyl)amine.

Compounds of the general formula I which contain basic groups, e.g. anamino group, an amidino group or a guanidino group, form salts withinorganic acids, such as e.g. hydrochloric acid, sulphuric acid orphosphoric acid and with organic carboxylic or sulphonic acid, such ase.g. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid,tartaric acid, methanesulphonic acid or p-toluenesulphonic acid.

The compounds of the general formula I according to the invention cancontain optically active carbon atoms and can thus be present in theform of pure enantiomers or in the form of enantiomer mixtures. Bothpure enantiomers and enantiomer mixtures and also diastereomers anddiastereomer mixtures are a subject of the present invention.

The compounds of the general formula I according to the invention canmoreover contain mobile hydrogen atoms, i.e. can be present in varioustautomeric forms. These tautomers are also a subject of the presentinvention.

Preferred compounds of the formula I are those in which Y denotes--(CH₂)_(m) CO--, where m stands for 1 or 2, or --CHR^(s) CO where R^(S)stands for the side chain of the amino acids alanine, valine,phenylalanine, tyrosine, leucine, isoleucine, tryptophan, lysine,histidine, asparagine, glutamine or phenylglycine, or ##STR11## r standsfor 1; W denotes --COW¹ ;

Z² denotes ##STR12## W¹ denotes hydroxyl, (C₁ -C₄)-alkoxy, in particularmethoxy, ethoxy, 2-propyloxy, isobutyloxy or tert-butyloxy, orbenzyloxy;

R denotes hydrogen;

R¹ denotes --(CH₂)_(n) --NH--X, where n stands for an integer from 1 to5, --(CH₂)_(p) --C₆ H₄ --(CH₂)_(q) --NH--X or --(CH₂)_(p) --C₆ H₄--(CH₂)_(q) --C(═NX)--NH₂, where p and q independently of one anotherstand for 0 or 1;

X denotes hydrogen, (C₁ -C₆)-alkoxycarbonyl, (C₁ -C₆)-alkylcarbonyl, (₁-C₁₈)-alkylcarbonyloxy-(C₁ -C₆)-alkoxycarbonyl, (C₆ -C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl or a radical of the fomula ##STR13## in which R' andR" independently of one another stand for hydrogen, trifluoroethyl, (C₁-C₆)-alkylcarbonyl, (C₁ -C₆)-alkoxycarbonyl, (C₁-C₁₈)-alkylcarbonyloxy-(C₁ -C₆)-alkoxycarbonyl or (C₆ -C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl;

X¹ denotes --(CH₂)_(q) --NH--X or --C(═NX)--NH₂, where q stands for 0 or1;

R² denotes hydrogen;

R³ denotes --CO--NH--R⁴, where --NH--R⁴ stands for the radical of anα-amino acid, its ω-amino-(C₂ -C₈)-alkylamide or its (C₁ -C₈)-alkyl orbenzyl ester, or where R⁴ denotes methyl which is substituted by anamino acid side chain and by a radical from the series --SO₂ --OH, --SO₂--NHR⁹ and tetrazolyl.

Radicals of α-amino acids standing for --NH--R⁴ are in this caseparticularly preferably the valine, lysine, phenylalanine, phenylglycineor 4-chlorophenylglycine radical. If --NH--R⁴ in this case stands for anester of one of these α-amino acids, the methyl, ethyl, isopropyl,isobutyl, tert-butyl ester or benzyl ester is preferred.

Compounds of the formula I can be prepared by fragment condensation of acompound of the general formula III ##STR14## with a compound of thegeneral formula IV ##STR15## where the radicals Z¹, Z², A, B, R, R², R³,Y and W and also r are defined as indicated above.

The starting compounds of the general formula IV are as a rulesynthesized stepwise from the C-terminal end. For condensation of thecompounds of the general formula III with those of the general formulaIV, the coupling methods of peptide chemistry known per se (see e.g.Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Volumes 15/1 and 15/2, Stuttgart, 1974) are advantageouslyused. For this coupling, it is as a rule necessary that amino groupscontained in R¹, R³ and W are protected by reversible protective groupsduring the condensation. The same applies to the carboxyl groups of thecompounds of the formula IV, which are preferably present as (C₁-C₆)-alkyl, benzyl or tert-butyl esters. Amino group protection isunnecessary if the amino groups to be generated are still present asnitro or cyano groups and are only formed, after coupling, byhydrogenation. After coupling, the protective groups present are removedin a suitable manner. For example, NO₂ groups (guanidino protection),benzyloxycarbonyl groups and benzyl esters can be removed byhydrogenation. The protective groups of the tert-butyl type are cleavedby acid, while the 9-fluorenylmethyloxycarbonyl radical is removed bymeans of secondary amines.

The starting compounds of the general formula III can be obtained, if Astands for --CHR¹ -- and B stands for --CH₂ -- and Z¹ and Z² stand for--CO--, as follows:

By reaction of succinic acid derivatives of the general formula V ortheir esters ##STR16## or of ethanetricarboxylic acid derivatives of thegeneral formula Va or their esters, where R¹ is defined as indicatedabove, ##STR17## with amino acids of the general formula VI orpreferably their methyl, ethyl, benzyl or tert-butyl esters,

    H.sub.2 N--Y--OH,                                          (VI)

where Y is defined as indicated above (see e.g. Houben-Weyl, Methodender organischen Chemie [Methods of Organic Chemistry], Volume 11/2 andE5).

The starting compounds of the general formula III can be obtained, if Astands for --NR¹ -- and B stands for oxygen and Z¹ and Z² stand for--CO-- or --CS--, as follows:

By reaction of hydroxylamine derivatives of the general formula VII,where R¹ is defined as indicated above,

    R.sup.1 --NH--OH                                           (VII)

with an isocyanato or isothiocyanato ester of the general formula VIII,where Z¹ and Y are defined as indicated above,

    Z.sup.1 ═N--Y--OCH.sub.3                               (VIII)

hydroxyurea derivatives of the general formula IX ##STR18## are obtainedwhich are cyclized by reaction with phosgene or thiophosgene and bysubsequent hydrolysis of the ester functions yield the compounds of thegeneral formula IIIa ##STR19##

During the cyclization, guanidino groups can be protected by protectivegroups, such as NO₂ or Mtr. Amino groups or amidino groups in the sidechain must also be present in protected form (for example as the Boc orZ derivative) or further as the NO₂ or cyano function, which can laterbe reduced to the amino group or, in the case of the cyano group, alsoconverted into the amidino group.

The starting compounds of the general formula III can be obtained, if Astands for --CHR¹ --, B stands for oxygen and Z¹ and Z² stand for--CO--, by reaction of compounds of the general formula X ##STR20##which can be prepared by processes known from the literature (see e.g.J. W. Clarke-Lewis, Chem. Rev. 58 (1958), 63; R. L. Dow et al., J. Med.Chem. 34 (1991), 1538 and literature cited there; EP-A 428 312), withcompounds of the general formula XI

    R.sup.10 --Y--OCH.sub.3,                                   (XI)

where R¹ and Y are defined as indicated above and R¹⁰ represents asuitable leaving group, and subsequent hydrolysis of the esterfunctions.

The starting compounds of the general formula III can be obtained, if Astands for --NR¹ -- and B stands for --CH₂ -- and Z¹ stands for --CO--and Z² stands for --CO--, as follows:

By reaction of compounds of the general formula XII

    R.sup.1 --NH.sub.2,                                        (XII)

where R¹ is defined as indicated above, with glyoxylic acid or itsesters, compounds of the general formula XIII ##STR21## are obtained,for example, under the conditions of reductive amination.

By reaction of the compounds of the general formula XIII with anisocyanato or an isothiocyanatocarboxylic acid ester, for example of thegeneral formula VIII, or of a corresponding carboxylic acid, ureaderivatives, for example of the general formula XIV ##STR22## areobtained which can be cyclized and hydrolysed to give compounds of thegeneral formula IIIb.

The starting compounds of the general formula III can be obtained, if Astands for --CHR¹ -- and B stands for --CH₂ -- and Z¹ stands for --CO--and Z² stands for --CH₂ --, as follows:

By N-alkylation of compounds of the general formula XV ##STR23## withcompounds of the general formula XI, where the compounds of the generalformula XV are obtainable by C-alkylation of 2-pyrrolidinone protectedon the nitrogen, with compounds of the general formula XVI

    R.sup.1 --R.sup.10,                                        (XVI)

in which R¹⁰ represents a suitable leaving group. Correspondingalkylation reactions of pyrrolidinones are described, for example, in M.A. E. Bowman et al., Org. Prep. Proced. Int. 22 (1990) 636; C. H.Kochbar et al., J. Org. Chem. 50 (1985) 3019; J. D. Stewart et al., J.Org. Chem. 52 (1987) 2113; T. J. Hagen, Synlett (1990) 63.

The starting compounds of the general formula III can be obtained, if Astands for --NR¹ -- and B stands for --CH₂ -- and Z¹ stands for --CO--or --CS-- and Z² stands for --CH₂ --, as follows:

By cyclization of compounds of the general formula XVII ##STR24## or,for example, of their esters with phosgene or thiophosgene or synthesisequivalents of phosgene or thiophosgene, compounds of the generalformula XVII being obtainable, for example, from compounds of thegeneral formula XVIII by a reductive amination (see e.g. W. S. Saari etal., J. Med. Chem. 33 (1990), 2590). Alternatively, compounds of thegeneral formula III, in which A stands for --NR¹ -- and B stands for--CH₂ -- and Z¹ stands for --CO-- and Z² stands for --CH₂ --, areobtained by successive N-alkylation of the compound of the formula XIX##STR25## with compounds of the general formula XI and compounds of thegeneral formula XVI.

The starting compounds of the general formula III can be obtained, if Astands for X¹ --C₆ H₄ --CH═C<, by condensation of compounds of thegeneral formula XX ##STR26## with the benzaldehydes of the generalformula XXI and subsequent alkylation with compounds of the generalformula XI.

In all reaction steps, functional groups which may be free must beprotected by suitable reversible protective groups, which are laterremoved again in a suitable manner.

For the guanylation and nitroguanylation of the amino compounds thefollowing reagents can be used:

1. O-Methylisourea (S. Weiss and H. Krommer, Chemiker Zeitung 98 (1974)17-618),

2. S-Methylisothiourea R. F. Borne, M. L. Forrester and I. W. Waters, J.Med. Chem. 20 (1977) 771-776),

3. Nitro-S-Methylisothiourea (L. S. Hafner and R. E. Evans, J. Org.Chem. 24 (1959) 1157),

4. Formamidinesulphonic acid (K. Kim, Y.-T. Lin and H. S. Mosher,Tetrahedron Lett. 29 (1988) 3183-3186),

5. 3,5-Dimethyl-1-pyrazolylformamidinium nitrate. (F. L. Scott, D. G.O'Donovan and J. Reilly, J, Amer. Chem. Soc. 75 (1953) 4053-4054),

6. N,N'-Di-tert-butyloxycarbonyl-S-methylisothiourea (R. J. Bergeron andJ. S. McManis, J. Org. Chem. 52 (1987) 700-1703),

7. N-Alkoxycarbonyl-, N,N'-dialkoxycarbonyl-, N-alkylcarbonyl- andN,N'-dialkylcarbonyl-S-methyl-isothiourea (H. Wollweber, H. Koing, E.Niemers, A. Widding, P. Andrews, H.-P. Schulz and H. Thomas, Arzneim.Forsch./Drug Res. 34 (1984) 531-542).

Amidines can be prepared from the corresponding cyano compounds byaddition of alcohols (e.g. methanol or ethanol) in acidic anhydrousmedium (e.g. dioxane, methanol or ethanol) and subsequent aminolysis (G.Wagner, P. Richter and Ch. Garbs, Pharmazie 29 (1974) 12-15). A furthermethod of preparing amidines is the addition of H₂ S to the cyano group,followed by a methylation of the resulting thioamide and subsequentreaction with ammonia (GDR patent no. 235 866).

The compounds of the general formula I and their physiologicallytolerable salts can be administered as medicines per se, in mixtureswith one another or in the form of pharmaceutical preparations whichpermit enteral or parenteral administration and which contain as activeconstituent an effective dose of at least one compound of the generalformula I or of a salt thereof, in addition to customarypharmaceutically innocuous excipients and additives. The preparationsnormally contain about 0.5 to 90% by weight of the therapeuticallyactive compound.

The medicines can be administered orally, e.g. in the form of pills,tablets, lacquered tablets, sugar-coated tablets, granules, hard andsoft gelatine capsules, solutions, syrups, emulsions or suspensions oraerosol mixtures. However, administration can also be carried outrectally, e.g. in the form of suppositories, or parenterally, e.g. inthe form of injection or infusion solutions or microcapsules,percutaneously, e.g. in the form of ointments or tinctures, or nasally,e.g. in the form of nasal sprays.

The pharmaceutical preparations are prepared in a manner known per se,pharmaceutically inert inorganic or organic excipients being used. Forthe preparation of pills, tablets, sugar-coated tablets and hardgelatine capsules, use can be made of e.g. lactose, maize starch orderivatives thereof, talc, stearic acid or its salts, etc. Excipientsfor soft gelatine capsules and suppositories are e.g. fats, waxes,semi-solid and liquid polyols, natural or hardened oils etc. Suitableexcipients for the preparation of solutions and syrups are e.g. water,sucrose, invert sugar, glucose, polyols etc. Suitable excipients for thepreparation of injection solutions are water, alcohols, glycerol,polyols, vegetable oils etc. Suitable excipients for microcapsules orimplants are copolymers of glycolic acid and lactic acid.

Besides the active compounds and excipients, the pharmaceuticalpreparations can also contain additives, such as e.g. fillers,extenders, disintegrants, binders, lubricants, wetting agents,stabilizers, emulsifiers, preservatives, sweeteners, colourants,flayoutings or aromatizers, thickeners, diluents, buffering substances,and further solvents or solubilizers or agents for achieving a depoteffect, and also salts for changing the osmotic pressure, coatingcompositions or antioxidants. They can also contain two or morecompounds of the general formula I or their pharmacologically acceptablesalts and additionally one or more other therapeutically activesubstances.

Other therapeutically active substances of this type are, for example,circulation-promoting agents, such as dihydroergocristine, nicergoline,buphenine, nicotinic acid and its esters, pyridylcarbinol, bencyclan,cinnarizine, naftidrofuryl, raubasine and vincamine; positivelyinotropic compounds, such as digoxin, acetyldigoxin, metildigoxin andlanatoglycosides; coronary dilators, such as carbochromen; dipyridamol,nifedipine and perhexiline; antianginal compounds, such as isosorbidedinitrate, isosorbide mononitrate, glycerol nitrate, molsidomin andverapamil; β-blockers, such as propranolol, oxprenolol, atenolol,metoprolol and penbutolol. Moreover, the compounds can also be combined,for example, with nootropically active substances, such as e.g.piracetam, or CNS-active substances, such as pirlindol, sulpiride etc.

The dose can vary within wide limits and is to be suited to theindividual conditions in each individual case. In general, in the caseof oral administration a daily dose of about 0.1 to 1 mg/kg, preferably0.3 to 0.5 mg/kg, of body weight is appropriate to achieve effectiveresults, in the case of intravenous administration, the daily dose is ingeneral about 0.01 to 0.3 mg/kg, preferably 0.05 to 0.1 mg/kg, of bodyweight.

The daily dose can be divided, in particular in the case of theadministration of relatively large amounts, into several, e.g. 2, 3 or4, part administrations. If appropriate, depending on individualbehaviour, it may be necessary to deviate upwards or downwards from thedaily dose indicated. Pharmaceutical preparations normally contain 0.2to 50 mg, preferably 0.5 to 10 mg, of active compound of the generalformula I or of one of its pharmaceutically acceptable salts per dose.

The novel heterocycles of the formula I according to the invention havethe ability to inhibit the binding of fibrinogen, fibronectin and thevon Willebrand factors to integrin receptors. In this manner, theyaffect the cell-cell and cell-matrix interaction and can thus preventthe formation of blood platelet thrombi. Integrins are cell membraneglycoproteins and mediate cell adhesion by interaction with a pluralityof extra-cellular proteins such as fibronectin, laminin, collagen,vitronectin, and von Willebrand factor or with other cell membraneproteins such as e.g. ICAM-1. An important receptor from the integrinfamily is the glycoprotein IIb/IIIa localized on blood platelets(fibrinogen receptor)--a key protein of platelet-platelet interactionand thrombus formation. A central fragment in the receptor recognitionsequence of these proteins is the tripeptide Arg-Gly-Asp (E. Ruoslahtiand M. D. Pierschbacher, Science 238 (1987) 491-497; D. R. Phillips, I.F. Charo, L. V. Parise and L. A. Fitzgerald, Blood 71 (1988) 831-843).

The heterocycles of the general formula I therefore find an applicationfor the prophylaxis and therapy of arterial vascular disorders such asacute myocardial infarct in combination with lysis therapy, post-infarcttreatment, secondary prevention of myocardial infarct, reocclusionprophylaxis after lysis and dilatation, unstable angina pectoris,transitory ischaemic attacks, stroke, coronary bypass operation andreocclusion prophylaxis of the bypass, pulmonary embolism, peripheralarterial occlusive diseases, disseminating aneurysms, for the therapy ofvenous and microcirculatory vascular disorders such as deep veinthrombosis, disseminated intravascular clotting, post-operative andpost-partum trauma, surgical or infectious shock, septicaemia, for thetherapy in disorders with hyperreactive platelets, thromboticthrombocytopenic purpura, preeclampsia, premenstrual syndrome, dialysis,extracorporal circulation; a further application is provided ininflammations and in the treatment of tumours. Osteoporosis can furtherbe prevented by inhibition of osteoclast binding to the bone surface.

The compounds are tested in particular for their inhibitory effect onblood platelet aggregation and the adhesion of fibrinogen to bloodplatelets. Gel-filtered blood platelets from human donor blood are used,which are activated with ADP or thrombin.

The inhibition of the binding of fibrinogen to its receptor(glycoprotein IIb/IIIa) on intact, gel-filtered human platelets by thecompounds according to the invention is tested. The K_(i) value of theinhibition of binding of ²⁵ I-fibrinogen after stimulation with ADP (10μM) is indicated. (Reference: J. S. Bennett and G. Vilaire, J. Clin.Invest. 64 (1979) 1393-1401; E. Kornecki et al., J. Biol. Chem. 256(1981), 5695-5701; G. A. Marguerie et al., J. Biol. Chem. 254 (1979)5357-5363; G. A. Marguerie et al., J. Biol. Chem. 255 (1980) 154-161.)

As a functional test, the inhibition of the aggregation of gel-filteredhuman platelets is measured after ADP or thrombin stimulation by thecompounds according to the invention. The IC₅₀ value of the inhibitionis indicated (reference: G. A. Marguerie et al., J. Biol. Chem. 254(1979), 5357-5363).

On testing of the inhibition of fibrinogen binding and the inhibition ofaggregation, the following results are obtained for the compounds of theexamples which follow:

    ______________________________________    Inhibition of platelet Inhibition of    aggregation            fibrinogen binding    Example           ADP (μM) thrombin (μM)                                   K.sub.i (μM)    ______________________________________     1     0.2         0.09        0.043    12     100         80    13     100         100    17     100         100    18     100         70    14     20          35    15     200         200    16     20          9    19     4           1    ______________________________________

EXAMPLES Example 1{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-aspartyl-L-phenylglycine

a) Synthesis of ethyl 4-(4-cyanobenzyl)-3,3-bisethoxycarbonylbutyrate

24.6 g of ethyl 1,1,2-ethanetricarboxylate are dissolved in 500 ml ofabs. ethanol and treated in portions with 11.2 g of potassiumtert-butoxide. 19.6 g of p-bromomethylbenzonitrile are added in portionsto this mixture. It is heated at about 60° C. for 5 hours. It is thenallowed to cool to room temperature, the precipitate is filtered off andthe filtrate is concentrated in vacuo. The oily residue which remains ischromatographed on silica gel usingdichloromethane/methanol/water/acetic acid (100:1(100:10:1:1). Theproduct fractions are combined and concentrated to dryness in vacuo. Anoil remains which slowly crystallizes.

Yield: 28.7 g

MS(CI): 362 [M+H]⁺

NMR(CDCl₃): δ=1.25 ppm (m, 9H); 2.82 ppm (s, 2H); 3.45 ppm (s, 2H); 4.20ppm (m, 6H); 7.25 ppm (d, 2H); 7.55 ppm (d, 2H).

b) Synthesis of ethyl4-[4-(aminoiminomethyl)benzyl]-3,3-bisethoxycarbonylbutyratehydrochloride

28.7 g of ethyl 4-(4-cyanobenzyl)-3,3-bisethoxycarbonylbutyrate aredissolved in 900 ml of abs. ethanol and cooled to -5° C. in a dry-icebath. Dry HCl gas is introduced into this solution, the temperaturealways being kept below 0° C. After about 4 h, the strongly exothermicreaction subsides and the reaction mixture is allowed to stand overnightat 0° C. The solvent is then stripped off in vacuo in a rotaryevaporator and the oily residue is dissolved in 200 ml of dryisopropanol and cautiously treated with NH₃ /isopropanol until themixture has reached pH 8. The mixture is stirred at 60°-70° C. for 3 hand allowed to stand overnight at room temperature. The cooled solutionis filtered and the filtrate is concentrated in vacuo and the oilyresidue is triturated with diethyl ether. The solid precipitate isfiltered off with suction and washed with diethyl ether. After drying ina desiccator 25.47 g remain.

MS(FAB): 379.2 [M+H]⁺

NMR(CDC₁₃): δ=1.25 ppm (m, 9H); 2.75 ppm (s, 2H); 3.40 ppm (s, 2H); 4.18ppm (m, 6H); 7.28 ppm (d, 2H); 7.88 ppm (d, 2H); 8.43 ppm (br s, 2H);ppm (br s, 2H). 9.33 (br s, 2H).

c) Synthesis of4-[4-(aminoiminomethyl)benzyl]-3,3-bisethoxycarbonylbutyric acidhydrochloride

11.34 g of ethyl4-[4-(aminoiminomethyl)benzyl]-3,3-bisethoxycarbonylbutyratehydrochloride are stirred in 250 ml of 6N HCl at 40° C. for 1 h and at80° C. for 2 h. The mixture is then allowed to stand overnight at roomtemperature and is concentrated to dryness in vacuo. The residue istaken up in a little water and freeze-dried.

Yield: 10.5 g

MS (FAB): 351.2 [M+H]⁺

d) Synthesis of{4-[4-(aminoiminomethyl)benzyl]-3,3-bisethoxycarbonylbutyryl}glycinemethyl ester hydrochloride

10.5 g of 4-[4-(aminoiminomethyl)benzyl]-3,3-bisethoxycarbonylbutyricacid hydrochloride are dissolved in 500 ml of dimethylformamide. 3.75 gof glycine methyl ester hydrochloride, 9.83 g ofO-[(cyanoethoxycarbonylmethylene)amino]-N,N,N',N'-tetramethyluroniumtetrafluoroborate (TOTU) and 11.5 ml of N-ethylmorpholine are then addedsuccessively. The mixture is stirred for 24 h and the solvent is thenstripped off in vacuo. The oily residue is chromatographed on silica gelusing dichloromethane/methanol/water/acetic acid (100:10:1:1). Thefractions containing the product are combined and concentrated.

Yield: 7.8 g

MS(FAB): 442.2

e) Synthesis of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acidhydrochloride

4 g of{4-[4-(aminoiminomethyl)benzyl]-3,3-bisethoxycarbonylbutyryl}glycinemethyl ester hydrochloride are heated under reflux in 100 ml of conc.HCl for 30 min, then the mixture is concentrated to dryness in vacuo,and the residue is redistilled twice with 10 ml of water and dried in ahigh vacuum.

Yield: 3 g

MS(FAB): 290.1 [M+H]⁺

f) Synthesis of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-(β-tert-butyl)aspartyl-L-phenylglycinetert-butyl ester

1.74 g of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acidhydrochloride are dissolved in 120 ml of DMF and treated successivelywith 2.49 g of H-Asp(OtBu)-Phg-OtBu, 2.95 g of TOTU and 3.45 ml ofN-ethylmorpholine. The mixture is stirred for 24 h and then concentratedto dryness. The oily residue which remains is chromatographed on silicagel using dichloromethane/methanol/water/acetic acid (100:10:1:1). Thecombined substance-containing fractions are concentrated. 0.98 gremains.

MS(FAB): 650.3 [M+H]⁺

g) Synthesis of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-aspartyl-L-phenylglycine

980 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-(β-tert-butyl)aspartyl-L-phenylglycinetert-butyl ester are treated with 20 ml of trifluoroacetic acid and,after allowing to stand for 20 min, the mixture is concentrated todryness. The residue is redistilled three times with some diethyl ether,then taken up in a little water and freeze-dried.

Yield: 398 mg

MS(FAB): 538.2 [M+H]⁺

¹ H-NMR (D₂ O): δ=2.51-3.51 ppm (m, 8H); 4.10-4.35 ppm (m, 2H); 5.45 (d,1H); 7.30-7.80 ppm (m, 9H)

Amino

acid analysis: Asp: 0.99 (1); Gly: 1.00 (1); Phg: 1.01 (1).

The following are obtained analogously:

Example 2{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-aspartyl-L-phenylalanineExample 3{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-l-yl}acetyl-L-aspartyl-L-valineExample 4{3-[4-(Aminoiminomethyl)phenyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-aspartyl-L-phenylglycineExample 52-{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}-propionyl-L-aspartyl-L-phenylglycineExample 6{2-[4-(Aminoiminomethyl)benzyl]-3,5-dioxo[1,2,4]oxadiazolidin-4-yl}acetyl-L-aspartyl-L-phenylglycineExample 7{5-[4-(Aminoiminomethyl)benzyl]-2,4-dioxo[1,3]oxazolidin-3-yl}-acetyl-L-aspartyl-L-phenylglycincExample 8{3-[4-(Aminoiminomethyl)phenyl]-2,5-dioxoimidazolidin-1-yl}-acetyl-L-aspartyl-L-phenylglycineExample 9[3-(3-Guanidinopropyl)-2,5-dioxopyrrolidin-1-yl]acetyl-L-aspartyl-L-phenylglycineExample 103-[3-(3-Aminopropyl)-2,5-dioxopyrrolidin-1-yl]benzoyl-L-aspartyl-L-phenylglycineExample 11<{{3-[4-(Amlnoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}-acetyl-L-aspartylamido}phenylmethylsulfonyl>ureaExample 12{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptophanmethyl ester

403 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acidhydrochloride are coupled with 356.6 mg of L-tryptophan methyl esterhydrochloride by the process described above. After working up andchromatographic purification, 270 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptophanmethyl ester are obtained.

MS (FAB): 490.2 [M+H]⁺

Example 13{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-D,L-homophenylalaninemethyl ester

403 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acidhydrochloride are coupled with 270 mg of D,L-homophenylalanine methylester by the process described above. After working up andchromatographic purification, 343 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}-acetyl-D,L-homophenylalaninemethyl ester are obtained.

MS(FAB): 465.2 [M+H]⁺

Example 14{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-(β-isopropyl)aspartyl-L-phenylglycineisopropyl ester

412 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acidhydrochloride are coupled with 500 mg ofL-(β-isopropyl)aspartyl-L-phenylglycine isopropyl ester by the processdescribed above. After working up and chromatographic purification, 330mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-(β-isopropyl)aspartyl-L-phenylglycineisopropyl ester are obtained.

MS(FAB): 622.4 [M+H]⁺

Example 15 Methyl3-(R,S)-3-<{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetamido>-3-(3-hydroxyphenyl)propionate

500 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl)acetic acidhydrochloride are coupled with 400 mg of methyl3-(R,S)-3-amino-3-(3-hydroxyphenyl)propionate hydrochloride by theprocess described above. After working up and chromatographicpurification, 78 mg of methyl3-(R,S)-3-<{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetamido>-3-(3-hydroxyphenyl)propionateare obtained.

MS (ES): 467.2 [M+H]⁺

Example 163-(R,S)-3-<{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetamido>-3-(3-hydroxyphenyl)propionate

50 mg of methyl3-(R,S)-3-<{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetamido>-3-(3-hydroxyphenyl)propionateare allowed to stand at room temperature for 1 h with ml of concentratedhydrochloric acid. The mixture is then concentrated to dryness in vacuo,and the residue is taken up in a little water and freeze-dried. 22 mg of3-(R,S)-3-<{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetamido>-3-(3-hydroxyphenyl)propionateare obtained.

MS(ES): 453.1 [M+H]⁺

Example 17{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-D,L-homophenylalanine

45 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-D,L-homophenylalaninemethyl ester are allowed to stand at room temperature for 1 h with 5 mlof concentrated hydrochloric acid. The mixture is then concentrated todryness in vacuo, and the residue is taken up in a little water andfreeze-dried. 24 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-D,L-homophenylalanineare obtained.

MS(FAB): 451.2 [M+H]⁺

Example 18{3-[4-(Aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptopha

204 mg of{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptophanmethyl ester are heated with 10 ml of 6N HCl for 3 min, then the mixtureis evaporated to dryness and the residue is redistilled twice withwater. The residue is taken up in a little water and freeze-dried. 68 mgof{3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptophanare obtained.

MS(FAB): 476.2 [M+H]⁺

Example 19{3-[Piperidin-4-yl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-aspartyl-L-phenylglycine

a) Synthesis of ethyl 4-(4-pyridyl)-3,3-bisethoxycarbonylbutyrate

24.6 g of triethyl 1,1,2-ethanetrlcarboxylate are dissolved in 900 ml ofabs. ethanol and treated in portions with 38.6 g of potassiumtert-butoxide. 29.8 g of 4-chloromethylpyridine hydrochloride suspendedin 400 ml of abs. ethanol are added to this mixture in portions. It isheated at about 50° C. for 5 h and allowed to stand at room temperatureovernight. The precipitate is then filtered off and the filtrate isconcentrated in vacuo. The oily residue which remains is chromatographedon silica gel using ethyl acetate. The clean fractions are combined andconcentrated to dryness in vacuo. An oil remains which slowlycrystallizes.

Yield: 19.7 g

MS (CI): 338 [M+H]⁺

NMR(CDCl₃): 1.25 ppm (m, 9H); 2.84 ppm (s, 2H); 3.40 ppm (s, 2H); 4.20ppm (m, 6H); 7.08 ppm (dd, 2H); 8.50 ppm (dd, 2H).

b) Synthesis of 4-(4-pyridyl)-3,3-bisethoxycarbonylbutyric acid

8.75 g of ethyl 4-(4-pyridyl)-3,3-bisethoxycarbonylbutyrate are stirredat 50°-60° C. in 500 ml of 6N HCl for 2 h. The mixture is thenconcentrated in vacuo and allowed to react again at 50°-60° C. with 500ml of 6N HCl for 2 h. It is then concentrated to dryness in vacuo andredistilled twice using a little toluene. The residue is taken up in alittle water and freeze-dried.

Yield: 9.31 g (still contains some triester)

MS(FAB): 310.1 [M+H]⁺

c) Synthesis of [4-(4-pyridyl)-3,3-bisethoxycarbonylbutyryl]glycinemethyl ester

9.27 g of 4-(4-pyridyl)-3,3-bisethoxycarbonylbutyric acid are dissolvedin 600 ml of dimethylformamide. 3.69 g of glycine methyl esterhydrochloride, 8.78 g of TOTU and 11.5 ml of N-ethylmorpholine are thenadded successively. The mixture is stirred for 24 h and the solvent isthen stripped off in vacuo. The oily residue is chromatographed onsilica gel using ethyl acetate. The fractions containing the product arecombined and concentrated.

Yield: 6.6 g

MS(FAB): 381.1 [M+H]⁺

d) Synthesis of [3-(4-pyridyl)-2,5-dioxopyrrolidin-1-yl]acetic acid

3.58 g of [4-(4-pyridylyl)-3,3-bisethoxycarbonylbutyryl]-glycine methylester are refluxed in 1000 ml of conc. HCl for 30 min, then the mixtureis concentrated to dryness in vacuo, redistilled five times with tolueneand dried in a high vacuum.

Yield: 2.75 g

MS(DCl): 249 [M+H]⁺

e) Synthesis of [3-(piperidin-4-yl)-2,5-dioxopyrrolidin-1-yl]acetic acid

2.8 g of [3-(4-pyridyl)-2,5-dioxopyrrolidin-1-yl]acetic acid aresuspended in 160 ml of acetic acid and hydrogenated in an autoclave at100° C. and a hydrogen pressure of 150 bar for 24 h using 100 mg of 5%rhodium on carbon as a catalyst. The catalyst is then filtered off andthe filtrate is concentrated to dryness in vacuo. The product thusobtained is taken up in a little water and freeze-dried.

Yield: 2.3 g

MS(ES): 255 [M+H]⁺

f) Synthesis of{3-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-2,5-dioxopyrrolidin-1-yl}aceticacid

100 mg of [3-(piperidin-4-yl)-2,5-dioxopyrrolidin-1-yl]-acetic acid aredissolved in 15 ml of DMF and treated with 87.3 mg of di-tert-butylcarbonate and 51 μl of triethylamine. After 1 h, the solvent is strippedoff in vacuo and the residue is partitioned between ether and water. Theether phase is dried over sodium sulphate and then concentrated invacuo. 120 mg of an oil remain, which is immediately further reacted.

MS (FAB): 377.2 [M+Na]⁺, 355.3 [M+H]⁺

g) Synthesis of{3-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-(β-tert-butyl)aspartyl-L-phenylglycinetert-butyl ester

110 mg of{3-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-2,5-dioxopyrrolidin-1-yl}aceticacid are dissolved in 15 ml of DMF and treated successively with 128.5mg of H-Asp(OtBu)-Phg-OtBu, 101.7 mg of TOTU and 120 μl ofN-ethylmorpholine. The mixture is stirred for 24 h and then concentratedto dryness. The oily residue which remains is chromatographed on silicagel using dichloromethane/methanol/water/acetic acid (100:10:1:1). Thecombined substance-containing fractions are concentrated. 90 mg remain,which are immediately further reacted.

MS(ES): 715 [M+H]⁺

h) Synthesis of{3-[piperidin-4-yl]-2,5-dioxopyrrolidin-1-yl}-acetyl-L-aspartyl-L-phenylglycine

90 mg of{3-[(1-tert-butyloxycarbonyl)-piperidin-4-yl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-(β-tert-butyl)aspartyl-L-phenylglycinetert-butyl ester are dissolved in 10 ml of trifluoroacetic acid, and thesolution is allowed to stand at room temperature for 20 min and is thenconcentrated to dryness. The residue is redistilled twice with somediethyl ether, dissolved in a little water and the solution isfreeze-dried.

Yield: 60 mg

MS(FAB): 503.4 [M+H]⁺

Example A

Emulsions containing 3 mg of active compound per 5 ml can be preparedaccording to the following recipe:

    ______________________________________    Active compound          0.06 g    Neutral oil              q.s.    Sodium carboxymethylcellulose                             0.6 g    Polyoxyethylene stearate q.s.    Pure glycerol            0.6 to 2 g    Aromatizers              q.s.    Water                    to 100 ml    (demineralized or distilled)    ______________________________________

Example B

Tablets can be prepared according to the following formulation:

    ______________________________________    Active compound        2 mg    Lactose                60 mg    Maize starch           30 mg    Soluble starch         4 mg    Magnesium stearate     4 mg                           100 mg    ______________________________________

Example C

The following composition is suitable for the preparation of softgelatine capsules containing 5 mg of active compound per capsule:

    ______________________________________    Active compound          5 mg    Mixture of triglycerides from coconut oil                            150 mg    Capsule contents        155 mg    ______________________________________

Example D

The following formulation is suitable for the preparation ofsugar-coated tablets:

    ______________________________________    Active compound         3 mg    Maize starch            100 mg    Lactose                 55 mg    Sec-calcium phosphate   30 mg    Soluble starch          3 mg    Magnesium stearate      5 mg    Colloidal silicic acid  4 mg                            200 mg    ______________________________________

Example E

Sugar-coated tablets, containing an active compound according to theinvention and another therapeutically active substance:

    ______________________________________    Active compound         6 mg    Propanolol              40 mg    Lactose                 90 mg    Maize starch            90 mg    Sec-calcium phosphate   34 mg    Soluble starch          3 mg    Magnesium stearate      3 mg    Colloidal silicic acid  4 mg                            270 mg    ______________________________________

Example F

Sugar-coated tablets, containing an active compound according to theinvention and another therapeutically active substance:

    ______________________________________    Active compound         5 mg    Pirlindol               5 mg    Lactose                 60 mg    Maize starch            90 mg    Sec-calcium phosphate   30 mg    Soluble starch          3 mg    Magnesium stearate      3 mg    Colloidal silicic acids 4 mg                            200 mg    ______________________________________

Example G

Capsules, containing an active compound according to the invention andanother therapeutically active substance:

    ______________________________________    Active compound        5 mg    Nicergoline            5 mg    Maize starch           185 mg                           195 mg    ______________________________________

Example H

Injection solutions containing 1 mg of active compound per ml can beprepared according to the following recipe:

    ______________________________________    Active compound         1.0 mg    Polyethylene glycol 400 0.3 mg    Sodium chloride         2.7 mg    Water for injection to    1 ml    ______________________________________

We claim:
 1. Heterocycles of the formula I ##STR27## in which Z¹ denotes##STR28## Z² denotes ##STR29## Y denotes --(CH₂)_(m) CO--, where mstands for an integer from 1 to 4, or ##STR30## r denotes an integerfrom 0 to 3; A denotes --CHR¹ --, --NR¹ -- or X¹ --C₆ H₄ --CH═C<;Bdenotes --CH₂ -- or --O--; W denotes --COW¹, or tetrazoly; W¹ denoteshydroxyl, (C₁ -C₂₈)-alkoxy, or (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkoxy; R denoteshydrogen or (C₁ -C₆)-alkyl; R¹ denotes --(CH₂)_(p) --C₆ H₄ --(CH₂)_(q)--NH--X or --(CH₂)_(p) --C₆ H₄ --(CH₂)_(q) --C(═NX)--NH₂, in which p andq independently of one another stand for a number from 0 to 3; X denoteshydrogen, (C₁ -C₆)-alkylcarbonyl, (C₁ -C₆)-alkoxycarbonyl, (C₁-C₁₈)-alkylcarbonyloxy-(C₁ -C₆)-alkoxycarbonyl, (C₆ -C₁₄ -aryl-(C₁-C₆)-alkoxycarbonyl, or a radical of the formula II

    R'--NH--C(═N--R")--,                                   (II)

where R' and R" independently of one another stand for hydrogen, (C₁-C₆)-alkoxycarbonyl, (C₁ -C₆)-alkylcarbonyl, (C₁-C₁₈)-alkylcarbonyloxy-(C₁ -C₆) alkoxycarbonyl, or (C₆ -C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl; X¹ denotes --(CH₂)_(q) --NH--X or --(CH₂)_(p)--C(═NX)--NH₂, in which p and q stand for a number from 0 to 3; R²denotes hydrogen, (C₁ -C₄)-alkyl or phenyl, where the (C₁ -C₄)-alkyl andthe phenyl can be unsubstituted or mono- or polysubstituted By identicalor different radicals from the series hydroxyl, amino, (C₁ -C₄)-alkoxy,imidazolyl, indolyl, pyrrolidinyl, hydroxypyrrolidinyl, phenyl orhalogen; R³ denotes hydrogen, --CO--N(CH₃)R⁴ or --CO--NH--R⁴ ; R⁴denotes (C₁ -C₂₈)-alkyl, which can optionally be mono- orpolysubstituted by identical or different radicals from the serieshydroxyl, hydroxycarbonyl, aminocarbonyl, (C₆ -C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl, amino, (C₁ -C₁₈)-alkoxy, (C₁ -C₁₈)-alkoxycarbonyl,(C₃ -C₈)-cycloalkyl, or by the radical R⁵, where R⁵ denotes optionallysubstituted (C₆ -C₁₄)-aryl, a radical R⁶ or a radical R⁶ CO--, where thearyl radical can be mono- or polysubstituted by identical or differentradicals from the series (C₁ -C₁₈)-alkyl, (C₁ -C₁₈)-alkoxy, halogen,nitro, amino or trifluoromethyl; R⁶ denotes --NR⁷ R⁸, --OR⁷, tetrazolyl,an amino acid side chain, a natural or unnatural amino acid, imino acid,or a dipeptide radical, and also their esters and amides, where freefunctional groups can optionally be protected by protective groupscustomary in peptide chemistry; R⁷ denotes hydrogen, (C₁ -C₁₈)-alkyl, or(C₆ -C₁₄)-aryl-(C₁ -C₈)-alkyl; R⁸ denotes hydrogen, (C₁ -C₁₈)-alkyl, (C₆-C₁₄)-aryl or (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkyl,and their physiologicallytolerable salts.
 2. Heterocycles according to claim 1, wherein in theformula IY denotes --(CH₂)_(m) CO--, where m stands for 1 or 2, or##STR31## r stands for 1; W denotes --COW¹ ; Z² denotes ##STR32## W¹denotes hydroxyl, (C₁ -C₄)-alkoxy, or benzyloxy; R denotes hydrogen; R¹denotes --(CH₂)_(p) --C₆ H₄ --(CH₂)_(q) --NH--X or --(CH₂)_(p) --C₆ H₄--(CH₂)_(q) --C(═NX)--NH₂, where p and q independently of one anotherstand for 0 or 1; X denotes hydrogen, (C₁ -C₆)-alkoxycarbonyl, (C₁-C₆)-alkylcarbonyl, (C₁ -C₁₈)-alkylcarbonyloxy-(C₁ -C₆)-alkoxycarbonyl,(C₆ -C₁₄)-aryl-(C₁ -C₆)-alkoxycarbonyl or a radical of the formula##STR33## in which R' and R" independently of one another stand forhydrogen, (C₁ -C₆)-alkylcarbonyl, (C₁ -C₆)-alkoxycarbonyl, (C₁-C₁₈)-alkylcarbonyloxy-(C₁ -C₆)-alkoxycarbonyl or (C₆ -C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl; X¹ denotes --(CH₂)_(q) --NH--X or --C(═NX)--NH₂,where q stands for 0 or 1; R² denotes hydrogen; R³ denotes --CO--NH--R⁴,where --NH--R⁴ stands for the radical of an α-amino acid, itsω-amino-(C₂ -C₈)-alkylamide or its (C₁ -C₈)-alkyl or benzyl ester, orwhere R⁴ denotes methyl which is substituted by an amino acid side chainand by a tetrazolyl radical.
 3. Heterocycles according to claim 2,wherein R³ denotes --CO--NH--R⁴, where --NH--R⁴ stands for the radicalof the α-amino acids valine, lysine, phenylalanine, phenylglycine or4-chlorophenylglycine, their ωamino-(C₂ -C₈)-alkylamides or their (C₁-C₈)-alkyl or benzyl esters.
 4. Heterocycles according to claim 3,wherein the (C₁ -C₈)-alkyl ester of the α-amino acids is the methyl,ethyl, isopropyl, isobutyl or tert-butyl ester.
 5. Process for thepreparation of compounds of the fomula I according to claim 1, wherein afragment condensation of a compound of the general fomula III ##STR34##with a compound of the general formula IV ##STR35## is carried out,where the radicals A, B, Z¹, Z², W, Y, R, R²,R³ and r are defined asindicated in claim
 1. 6. Pharmaceutical preparation comprising one ormore compounds of the formula I according claim 1 and/or one or morephysiologically tolerable salts thereof as active compound together withpharmaceutically acceptable excipients and additives and optionally alsoone or more other pharmacological active compounds.
 7. Process forinhibiting platelet aggregation, the metastasis of carcinoma cells orosteoclast binding to the bone surface, which comprises administering toa patient in need thereof an effective dose of a compound of the formulaI according to claim
 1. 8. Heterocycles according to claim 2 in which W¹denotes a (C₁ -C₄)-alkoxy radical selected from the group consisting ofmethoxy, ethoxy, 2-propyloxy, isobutyloxy and tert-butyloxy.